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A Novel Topical PPARγ Agonist Induces PPARγ Activity in Ulcerative Colitis Mucosa and Prevents and Reverses Inflammation in Induced Colitis Models
- Source :
- Inflammatory Bowel Diseases, Inflammatory Bowel Diseases, Lippincott, Williams & Wilkins, 2018, 24 (4), pp.792-805. ⟨10.1093/ibd/izx079⟩
- Publication Year :
- 2018
- Publisher :
- Oxford University Press (OUP), 2018.
-
Abstract
- International audience; Background: Peroxisome proliferator-activated receptor-gamma (PPAR gamma) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPAR. agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)-and trinitrobenzene sulfonic acid (TNBS)-induced colitis. Methods: Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPAR gamma-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPAR gamma agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis. Results: AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-alpha, IL-1 beta, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-alpha, IL-1 beta , and IL-13 levels. Conclusions: AS002 triggers anti-inflammatory PPAR. activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.
- Subjects :
- Adult
Male
0301 basic medicine
Colon
Perilipin 2
Pharmacology
Inflammatory bowel disease
Perilipin-2
Rosiglitazone
03 medical and health sciences
Intestinal mucosa
inflammatory bowel disease
medicine
Animals
Humans
Immunology and Allergy
Intestinal Mucosa
Colitis
Aged
Peroxidase
ulcerative colitis
Mice, Inbred BALB C
biology
business.industry
animal model
Dextran Sulfate
Gastroenterology
Middle Aged
medicine.disease
Ulcerative colitis
3. Good health
PPAR gamma
030104 developmental biology
Trinitrobenzenesulfonic Acid
Myeloperoxidase
biology.protein
Cytokines
Colitis, Ulcerative
Female
business
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Ex vivo
medicine.drug
Subjects
Details
- ISSN :
- 15364844 and 10780998
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Inflammatory Bowel Diseases
- Accession number :
- edsair.doi.dedup.....035caee86726c54d7124a8adae61403c